The candidate is a trained human immunologist transitioning to the field of chronic lung disease. Her long-term career goals are to continue research in chronic lung disease as an independently funded investigator on tenure track. She will develop a research program emphasizing the role of the adaptive immune system in disease pathogenesis and to clearly define the mechanisms that regulate pathogenesis. For the last two years, she has studied the role of mycobacterial antigens in sarcoidosis disease pathogenesis in Dr. Wonder Drake's laboratory at Vanderbilt University Medical Center. In the proposed research plan, the candidate will use sarcoidosis as model system to investigate the role of CD8+ T cells in granulomatous inflammation. Sarcoidosis is a multisystem granulomatous disease of unknown etiology that involves the lungs in over 90% of affected individuals. Recent reports from independent laboratories have postulated mycobacteria as a candidate. The potential role of mycobacteria in sarcoidosis immunopathogenesis has been demonstrated by the detection of mycobacterial proteins and nucleic acids in sarcoidosis granulomas, as well as humoral and peripheral cellular immune responses to mycobacterial antigens in sarcoidosis subjects. In addition, the Drake laboratory has made significant advances in studying the immune response to mycobacterial antigens at the site of active sarcoidosis involvement - the lungs. Recently, we demonstrated the presence of antigen-specific recognition of mycobacterial proteins in both CD4+ and CD8+ T cells derived from sarcoidosis subjects at diagnostic bronchoscopy. The unexpected finding of antigen-specific CD8+ T cells suggested that CD8+ T cells may play an important role in sarcoidosis pathogenesis. It is my objective to delineate CD8+ molecular and biologic T cell function in sarcoidosis pathogenesis and how it influences sarcoidosis resolution or progression. The following three specific aims are intended to test the hypothesis that regulation and function of CD8+ T cells modulates disease outcome. We will test this hypothesis by pursuing the following Specific Aims. Specific Aim 1. To investigate pulmonary CD8+ T cell phenotype and function in sarcoidosis lung pathogenesis. Specific Aim 2. To investigate the molecular mechanisms associated with CD8+ T cell biologic function. Specific Aim 3. To perform a longitudinal investigation of the molecular basis of CD8+ T cell contribution to sarcoidosis pathogenesis. The proposed research will provide essential information concerning the role and function of CD8+ T cells in sarcoidosis resulting in novel approaches to treatment and potentially the reversal of disease progression. Investigation will be completed at Vanderbilt University School of Medicine, in the context of the Department of Microbiology and Immunology, with facilities and resources ideally suited for the immunologic and molecular analyses involved in this research. To support the candidate's career development, Dr. Wonder Drake (Assistant Professor, Vanderbilt University) and Dr. Luc Van Kaer (Professor, Vanderbilt University) will serve as co-mentors. Dr. Luc Van Kaer has a strong mentoring record and is a renowned T cell immunologist, while Dr. Wonder Drake is a leader in the sarcoidosis research field. In addition, the candidate has established a mentoring committee which consists of several accomplished researchers: 1) Spyros Kalams, MD (Associate Professor, Vanderbilt University), accomplished human T cell immunologist with a strong focus on CD8+ T cells, 2) James Crowe, MD (Professor, Vanderbilt University), a leading human immunologist and Director of the Flow Cytometry and Human Immunology Shared Resource, 3) JoAnne Flynn, PhD (Professor, University of Pittsburgh), distinguished researcher of granulomatous inflammation, particularly due to mycobacteria, and 4) Lee Newman, MD MPH (Professor, University of Colorado Health Sciences Center), accomplished sarcoidosis researcher. The mentored training that the candidate will receive during completion of this proposed research will provide her with the skills and career development opportunities necessary to establish an independent academic research program and to secure funding as an independent investigator. PUBLIC HEALTH RELEVANCE: Sarcoidosis is an inflammatory disease that involves the lungs in over 90% of affected individuals. The goal of this proposal is to investigate the contribution of CD8+ T cell biologic function to sarcoidosis pathogenesis. Understanding the role of CD8+ T cells in sarcoidosis pathogenesis will reveal biomarkers associated with disease outcome and potentially identify new therapeutic interventions resulting in improved treatment strategies for sarcoidosis patients. (End of Abstract)